Process for preparing isomers of salbutamol

ABSTRACT

A process for making opticallyOptically pure (R) and (S) salbutamol comprises obtaining the (R) or (S) isomer of either salbutamol or a salbutamol precursor in substantially optically pure formis obtained by resolving a racemic or optically impure mixture of enantiomers of salbutamol or of saida salbutamol precursor with either (L) or (D) tartaric acid, and where necessary converting said isomer of said precursor into either (R) or (S) salbutamol respectively; then optionally converting said optically pure (R) and/or (S) salbutamol into a pharmaceutically acceptable salt.

This application is a divisional of reissue application Ser. No.12/026,790, filed Feb. 6, 2008, which is a reissue of U.S. patentapplication Ser. No. 10/450,155, filed Sep. 15, 2003, now U.S. Pat. No.6,995,286, which is a §371 Application of International Application No.PCT/GB01/05444, filed on Dec. 10, 2001, claiming the which claimspriority of Great Britain Application No. 0030171.3, filed Dec. 11,2000, the. The entire disclosures of which the priority applicationslisted above are incorporated herein by reference in their entireties.

This invention relates to an improved method of making optically pure(R) and (S) salbutamol, also known as (R) and (S) albuterol. Thechemical name for salbutamol isα-[[(1,1-dimethyl-ethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol.

For certain medical conditions such as asthma, the (R) isomer ofsalbutamol (which is laevorotatory, denoted (−) or (l) is known to bevery much more potent therapeutically than the dextrorotatory (S)isomer. The R isomer of salbutamol is also known as levalbuterol. Onemethod of preparing the (R) and (S) isomers of salbutamol in opticallypure form is disclosed in U.S. Pat. No. 5,545,745. In this method,either of two precursor compounds for salbutamol is resolved using asubstituted tartaric acid derivative. Specifically the resolvingcompound used in U.S. Pat. No. 5,545,745 is chosen from(−)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid,(−)-di-benzoyl-L-tartaric acid and (+)-di-benzoyl-D-tartaric acid.Another reference (Hartley et al, Journal of Medicinal Chemistry, 1971,Vol 14, No 9, pp 895-896) describes much the same thing as U.S. Pat. No.5,545,745: the resolution is performed with either (+) or (−)di-para-toluoyl tartaric acid. A more recent publication (WO 99/42460)describes the resolution of a new ketal derivative of salbutamol(specifically 2-(N-t-butylamino)-1-(+2,2-dimethyl-1,2-benzodioxin-6-yl)ethanol). The resolution is again performed with a chiral tartaric acidderivative, such as (+) or (−) di-para-toluoyl tartaric acid or (+) or(−) di-O-benzoyl tartaric acid. Enantiomers of salbutamol can beproduced if desired, via a complicated, multi-stage process involvingresolution of the ketal derivative. The disadvantage of the processdescribed in WO 99/42460 is that the enantiomeric excess of the saltsobtained is low (based on the values given in the Examples). Thisrequires additional crystallizations, thus lowering the overall yields.Further, two additional synthetic steps of ketalization and hydrolysisfurther reduces the economic viability of the process.

Whilst the process of U.S. Pat. No. 5,545,745 is an improvement overprevious methods of resolution, it nevertheless has certaindisadvantages. The substituted tartaric acid derivatives employed areexpensive (and not readily available) and so need to be speciallyprepared or bought, which adds to the overall time and cost of theprocess. These resolving compounds are generally not recovered from theprocess and this further contributes to the costs.

We have now found a way of substantially overcoming these problems. Inparticular, we have found an economical and efficient method ofresolving salbutamol into its optically pure (R) and (S) isomers, whichmethod does not require the use of expensive substituted tartaric acidderivatives.

According to the present invention, there is provided a process formaking optically pure (R) and/or (S) salbutamol or pharmaceuticallyacceptable salts thereof, which process comprises obtaining the (E) (R)or (S) isomer of either salbutamol or a salbutamol precursor insubstantially optically pure form by resolving a racemic or opticallyimpure mixture of enantiomers of salbutamol or of said precursor witheither (L) or (D) tartaric acid, and where necessary converting saidisomer of said precursor into either (R) or (S) salbutamol respectively;then optionally converting said optically pure (R) and/or (S) salbutamolinto a pharmaceutically acceptable salt.

Unlike the substituted tartaric acid derivatives used in U.S. Pat. No.5,545,745, (L) and (D) tartaric acid are readily available andinexpensive. They can be recovered and re-used in the process ifdesired, although even when they are not re-used the process is muchmore economical than that described in U.S. Pat. No. 5,545,745.

An advantage of the present method is its general applicability todifferent intermediates of salbutamol. It also enables chirally pureproduct to be obtained in a good yield.

In a highly preferred aspect of the invention, the compound 4-benzylalbuterol (i) (α-[[(1,1- dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedimethanol) is used as thesalbutamol precursor. A racemic or optically impure mixture of thecompound is resolved to give the (R) and (S) isomers before conversionto the desired isomer of salbutamol takes place. 4-benzyl albuterol isreadily available commercially, for example from Cipla Limited.

The precursor 4-benzyl albuterol is typically prepared, for example,from the ester intermediatemethyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate(II).

This compound (II) can also, if desired, serve as the “salbutamolprecursor” which is itself resolved into its (R) and (S) isomers.

We have found that the present method of resolution can be usedsatisfactorily to resolve racemic salbutamol (or an optically impuremixture of enantiomers of salbutamol) itself.

Thus, in a further aspect, the invention provides a process for makingoptically pure (R) and/or (S) salbutamol or pharmaceutically acceptablesalts thereof, which process comprises resolving racemic salbutamol, oran optically impure mixture of enantiomers of salbutamol, with either(L) or (D) tartaric acid, and optionally converting said optically pure(R) and/or (S) salbutamol into a pharmaceutically acceptable saltthereof.

The present invention thus provides several ways of producing (R) and/or(S) salbutamol: by resolution at the final stage, for example on racemicsalbutamol, or by resolution at an intermediate stage—for example, byresolution of the alcohol intermediate 4-benzyl albuterol or byresolution of the ester intermediate (II)methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate.

We prefer to operate the process using (L) tartaric acid, since thisresults in the more active isomer (R) salbutamol. However, the inventionencompasses the production of (S) salbutamol, in which case (D) tartaricacid is used in the resolution step.

By the term “optically pure”, we mean an enantiomeric excess (e.e.)(which is a measure well known in the art) of about 95% or more. Theterm “optically impure” refers to mixtures of enantiomers where the e.e.value is below about 95%, but where the mixture is not exactly racemic.We have found that the resolution step with (L) or (D) tartaric acid isvery efficient, generally giving an e.e. value of 99% or more for thechosen isomer.

Operation of the process using our preferred precursor 4-benzylalbuterol is preferably carried out according to the following Scheme Abelow:

In step (a) a suspension of racemic 4-benzyl albuterol is mixed with asolution of either (L) or (D) tartaric acid (as desired) in an organicsolvent. We prefer to use a solvent such as methanol, ethanol,isopropanol, acetone or ethyl acetate or a mixture of two or morethereof. The mixture is then chilled to give crystals of the (L) or (D)tartrate salt of 4-benzyl albuterol, which are then separated andpurified. The yield of the chosen tartrate salt is generally above 30%,with an e.e. value of around 99%.

In step (b), the optically pure isomer of either (R) or (S) 4-benzylalbuterol is obtained from a solution (typically aqueous) of thecorresponding tartrate salt. We prefer to liberate the free base fromthe tartrate salt by the gradual addition of alkali to the solution ofthe salt, for example by using sodium hydroxide or sodium carbonate.Other bases that can be used include potassium hydroxide, potassiumcarbonate, aqueous ammonia and sodium or potassium bicarbonate.Prolonged stirring of the alkali/salt mixture is usually necessary toprecipitate the free base completely from the solution. The yield of the(R) or (S) isomer of 4-benzyl albuterol is generally 40% or more basedon the quantity of racemic starting material. The e.e. value remainshigh, typically at 99% or more.

In step (c), (R) or (S) 4-benzyl albuterol free base is de-benzylated inorder to give (R) or (S) salbutamol. This is preferably carried out bysuspending the isomer of 4-benzyl albuterol in an organic solvent suchas ethanol, adding a palladium on carbon catalyst and hydrogenating thesuspension under pressure in a hydrogenator. The resulting opticallypure isomer of salbutamol is then filtered off. If desired, apharmaceutically acceptable salt of the free base can be obtained by theaddition of an acid (for example, dilute sulphuric or hydrochloric acid)in the usual way (see step (d)).

Alternatively, the resolving-step can if desired be carried out earlierin the process, for example, by resolving the ester intermediate (II).(L) or (D) tartaric acid may be used for the resolution, althoughpreferably (L) tartaric acid is employed so as to give the (R) form ofthe ester. This preferred route is shown in Scheme B below.

The reduction of the (R) isomer of the ester to (R) 4-benzyl albuterolcan, for example, be carried out using lithium aluminium hydride,although any suitable reducing agent can be used. The resolution istypically carried out in the same way as that described for 4-benzylalbuterol.

Other salbutamol precursors which can be usefully employed in theprocess of the invention include derivatives of 4-benzyl albuterol inwhich the ring of the benzyl group is variously substituted. The benzylgroup may, for example, be substituted with one or more halogen atoms(such as, chlorine, fluorine or bromine) or one or more alkoxy groupssuch as methoxy. Other similar substitutions which have the purpose ofprotecting the phenolic group of the salbutamol precursor may also beused, as will be clear to those skilled in the art.

The following examples are intended to illustrate the invention:

EXAMPLE 1

Preparation of R-4-Benzyl Albuterol-L-tartrate:

Racemic 4-benzyl albuterol (100 g, 0.30 mole) is suspended in methanol(500 ml) and heated to reflux. A solution of L-tartaric acid (50 g, 0.33mole) in methanol (150) ml is introduced in about 15 minutes. The clearsolution is then chilled to 0 to 5° C. and the crystals are filtered.The wet crystals are taken up in isopropanol (300 ml) and heated toreflux, cooled to room temperature and filtered to obtain the titlecompound as a white solid (65 g, 45% yield, 99% ee)

EXAMPLE 2

Preparation of R(−)-4-Benzyl Albuterol:

The product from Example 1 (65 g, 0.13 mole) is dissolved in water (650ml) and filtered over celite to remove insolubles. The clear filtrate iscooled to 10° C. and a solution of 10% sodium hydroxide (80 ml) isslowly introduced. The sticky solid precipitated becomes free onprolonged stirring for 4 hours. The solid is filtered, washed with waterand dried to obtain the title compound as a white solid (40 g, 40% yieldbased on amount of racemic compound, 99% e.e.).

EXAMPLE 3

Preparation of R(−) Salbutamol Sulphate:

R-4-Benzyl Albuterol (40 g, 0.12 mole) is suspended in 500 ml ethanol,5% palladium on carbon (2 g) is added and shaken in a 1 lit. ParrHydrogenator at 30 psi for 2 hours. The catalyst is filtered off and theclear filtrate is cooled to 15° C. under stirring. Sulphuric acid (4.9g, 0.05 mole) is introduced dropwise and the resulting mixture isstirred for 1 hour and filtered. The solids are washed with ethanol (20ml) and dried at 45 to 50° C. in a vacuum oven to give pure R-salbutamolsulphate (30 g, 86% yield).

EXAMPLE 4

Preparation of R(−) methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate:

Racemic ester (100 g, 0.28 mole) is suspended in methanol (600 ml) andheated to reflux. A solution of L-tartaric acid (50 g, 0.33 mole) inmethanol (150 ml) is introduced in about 30 minutes. The clear solutionis then chilled to 0 to 5° C. and the crystals are filtered. The wetcrystals are taken up in ethanol (400 ml) and heated to reflux, cooledto room temperature and filtered to obtain the R(−) ester-L-tartrate asa white solid. This is then dissolved in water (500 ml) and filteredover celite to remove insolubles. The clear filtrate is then cooled to 0to 5° C. and an aqueous ammonia solution is introduced so as to obtain apH of 8.5 to 9. The mass is then stirred for 3 hours and the solidsfiltered, washed with water and dried to obtain the title compound (38g; 38% yield based on racemic compound, 99% e.e.).

EXAMPLE 5

Preparation of R(−)-4-benzyl Albuterol Using R(−)ester of Example 4:

R(−)-ester (35.8 g, 0.1 mole) is suspended in dry tetrahydrofuran (250ml) and cooled to 0 to 5° C. Lithium aluminium hydride (4 g; 0.33 mole)is introduced slowly and the reaction mass is further stirred for 3hours. A 15% sodium sulphate (20 ml) is then introduced and theprecipitate is then filtered off. The clear filtrate is thenconcentrated, taken up in ethyl acetate (100 ml), cooled to 5° C. andfiltered to obtain the title compound (30 g; 91%; 99% e.e.).

EXAMPLE 6

Preparation of (S)4-benzyl Albuterol-(D)-tartrate

Racemic 4-benzyl albuterol (100 g, 0.30 mole) is suspended in methanol(500 ml) and heated to reflux. A solution of (D-)tartaric acid inmethanol (150 ml) is introduced in about 15 minutes. The clear solutionis then chilled to 0 to 5° C. and the crystals filtered. The wetcrystals are taken up in isopropanol (300 ml) and heated to reflux,cooled to room temperature and filtered to obtain the title compound asa white solid (65 g; 45%; 99% e.e.).

EXAMPLE 7

Preparation of (S)-4-benzyl Albuterol:

The product from Example 6 (65 g; 0.13 mol) is dissolved in water (650ml) and filtered over celite to remove insolubles. The clear filtrate iscooled to 10° C. and a solution of 10% sodium hydroxide (80 ml) isslowly introduced. The solids thus precipitated are filtered, washedwith water and dried to obtain the title compound as a white solid (40g; 40% based on racemic compound, 99% c.c.).

EXAMPLE 8

Preparation of (S)-salbutamol Sulphate:

(S)-4- benzyl albuterol (40 g; 0.12 mole) is suspended in 500 mlethanol, 5% palladium on carbon (2 g) is added and shaken in a 1 litreParr hydrogenator at 30 psi for 2 hours. The catalyst is then filteredoff and the clear filtrate is cooled to 15° C. Sulphuric acid (4.9 g;0.05 mole) is added dropwise and the resultant mixture is stirred for 1hour and filtered. The solids are washed with ethanol (20 ml) and driedto give pure (S)-salbutamol sulphate (30 g; 86%).

EXAMPLE 9

Salbutamol (100 g; 0.41 mole) is dissolved in a 1:1 mixture of ethylacetate and methanol (500 ml) at about 70° C. To this solution is addedL(+)tartaric acid (66 g; 0.44 mole) under stirring. The contents aremaintained at 70° C. for 2 hours. On cooling, the tatrate saltcrystallises. This is filtered and recrystallised from ethanol to give52 g of the pure R (−) salbutamol tartrate. The salt is then suspendedin methanol (200 ml) and a solution of sodium methoxide (15 g; 0.27mole) in methanol is introduced. The precipitated solids are filteredoff and the filtrate is cooled to 10° C. Sulphuric acid is added slowlyto obtain a pH of the reaction mass between 4 to 4.5. The solids arefiltered and dried to obtain R(−)salbutamol sulphate (30 g).

1. A process for making optically pure (R) salbutamol orpharmaceutically acceptable salts thereof having a value of 95%enantiomeric excess or more, which process comprises obtaining the (R)isomer of either salbutamol or a salbutamol precursor, wherein thesalbutamol precursor is 4-benzyl albuterol ormethyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoatein optically pure form by: a) dissolving a mixture of salbutamol,4-benzyl albuterol ormethyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoateenantiomers and a molar excess (with respect to said salbutamol or saidprecursors) of (L) tartaric acid in a solvent; b) allowing the solutionto cool to crystalize a salt of one enantiomer; c) separating the saltfrom the solution; d) liberating the enantiomer from the salt; e) whenthe enantiomer is 4-benzyl albuterol ormethyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate,reducing the enantiomer; and f) except when salbutamol is used in stepa), debenzylating the enantiomer and recoVering the (R) enantiomer ofsalbuamol; then optionally converting said optically pure (R) salbutamolinto a pharmeucedically acceptable salt.
 2. A process according to claim1, wherein the mole equivalent amount of tartaric acid is greater thanor equal to 1.07.
 3. A process according to claim 1, wherein the moleequivalent amount of tartaric acid is greater than or equal to 1.1.
 4. Aprocess according to claim 1, wherein the mole equivalent amount oftartaric acid is at least 1.18.
 5. A process according to claim 1,wherein the salbutamol precursor is 4-benzyl albuterol.
 6. A processaccording to claim 1, wherein the resolution is carried out on racemicsalbutamol or on an optically impure mixture of enantiomers ofsalbutamol.
 7. A process according to claim 1, wherein the opticalpurity has a value of 99% enantiomeric excess or more.
 8. A processaccording to claim 1, further comprising converting said isomer of saidprecursor into either (R) salbutamol respectively; then optionallyconverting said optically pure (R) salbutamol into a pharmaceuticallyacceptable salt.
 9. Pure and isolated Levalbuterol L-tartrate having anenantiomeric excess of at least 95%.
 10. Levalbuterol L-tartrate asclaimed in claim 9, which is in crystalline form.
 11. An optically-pure4-benzyl albuterol salt of tartaric acid, selected from the groupconsisting of optically pure (R)-4-benzyl albuterol-(L)-tartrate saltand optically pure (S)-4-benzyl-albuterol-(D)-tartrate salt.
 12. Theoptically-pure 4-benzyl albuterol salt of tartaric acid of claim 11,where the optically pure (R)-4-benzyl albuterol-(L)-tartrate salt ispresent in an enantiomeric excess of greater than about 99%.
 13. Theoptically-pure 4-benzyl albuterol salt of tartaric acid of claim 11,where the optically pure (S)-4-benzyl albuterol-(D)-tartrate salt ispresent in an enantiomeric excess of greater than about 99%.
 14. Anoptically-puremethyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoatesalt of tartaric acid, selected from the group consisting of opticallypure(R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate(L)-tartratesalt and optically pure(S)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(D)-tartratesalt.
 15. The optically-puremethyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoatesalt of tartaric acid of claim 14, where the optically pure(R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(L)-tartratesalt is present in an enantiomeric excess of greater than about 99%. 16.The optically-puremethyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoatesalt of tartaric acid of claim 14, where the optically pure(S)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(D)-tartratesalt is present in an enantiomeric excess of greater than about 99%. 17.A pure and isolated salbutamol salt of tartaric acid having anenantiomeric excess of at least 95% selected from the group consistingof (R)-salbutamol-(L)-tartrate salt and (S)-salbutamol-(D)-tartratesalt.
 18. The pure and isolated salbutamol salt of tartaric acid ofclaim 17, where the (R)-salbutamol-(L)-tartrate salt is present in anenantiomeric excess of greater than about 99%.
 19. The pure and isolatedsalbutamol salt of tartaric acid of claim 17, where the(S)-salbutamol-(D)-tartrate salt is present in an enantiomeric excess ofgreater than about 99%.